This K24 application entitled ?Patient-Oriented Research (POR) in Arginine (Arg) Deficiency Syndromes? seeks 5 years of support for protected time to expand the principle investigator's (PI) mentoring activities, promote her career development & provide momentum to advance the applicant's research evaluating Arg therapy in sickle cell disease (SCD) and beyond. Arg is a nutritional supplement & obligate substrate for the production of nitric oxide, a potent vasodilator that becomes depleted during episodes of SCD-related pain and contributes to vaso- occlusion. The PI has completed a single-center randomized, double-blinded, placebo-controlled trial (RCT) of Arg therapy in 54 children with pain requiring hospitalization. She observed a reduction in opioid usage by over 54%, lower pain scores, and a clinically relevant trend towards decreased length of hospital stay in children who received 5 days of Arg therapy compared to placebo. She has an active research program that includes a FDA- sponsored Phase 2 RCT and a NHLBI-supported pharmacokinetics study of Arg therapy to treat SCD-related pain that is currently enrolling patients. The PI proposes to extend these studies to a definitive multi-center Phase 3 trial. Pain in SCD is the leading cause of hospitalizations, emergency room (ED) visits, missed school & is associated with an increased mortality rate. There are no current therapies to treat the underlying mechanisms of pain, with interventions limited to hydration and analgesia. The PI hypothesizes that Arg is a safe & inexpensive nutritional supplement with narcotic-sparing effects in pediatric SCD patients and pain. Her current and future study aims will determine the safety & efficacy of arginine therapy to reduce time to pain crisis resolution and total parenteral opioid use (mg/kg) in children with SCD & pain. This proposal will provide essential data for product development and will ultimately help gain FDA product approval for SCD if benefits of Arg therapy are confirmed in follow-up studies. Acute care of patients with SCD & pain in the ED is a neglected area of research. The results of this proposal may ultimately lead to a change in clinical practice for patients with SCD in both the ED & inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of pain are needed in SCD. In addition, the PI is highly committed to performing POR focused on nutrition science & in growing her mentorship reach to include a diverse group of undergraduate's, graduate & medical students, post- doctoral fellows & junior faculty in clinical nutrition research, having mentored scholarly activity for over 35 mentees already during the course of her career. During the 5-year grant, the candidate will also participate in a number of mid-career leadership & mentorship courses, choosing curriculums that will help advance the candidate as an educational leader & mentor within academic medicine. The environment at Emory University is ideal to foster these goals, and will enhance the career development of the applicant as a mentor champion in integrative medicine in partnership with the Atlanta Clinical and Translational Science Institute, thereby enabling her to train mentees in the field and increase the pool of evidence-based integrative clinical scientists.